Estrogen deficiency in the perimenopausal and menopausal woman is manifested by both short-term symptoms and long-term system illnesses. In the short term, the majority of women experience hot flushes and sweats associated with arousal from sleep. In addition, urogenital atrophy, decreased skin collagen and impaired balance may occur. Long-term, estrogen deficiency is associated with osteoporosis, heart disease, and possibly an increased risk of Alzheimer's disease in many women. Estrogen replacement therapy (ERT) is associated with clinical improvement in both short-term and long-term estrogen deficiency problems. Although there is a vast amount of data on the beneficial effects of estrogen on surrogate markers of potential cardiovascular benefit in molecular biology experiments and in animal and short-term human experiments, the clinical data related to long term prevention of disease is not always as expected. For example, a protective effect of estrogen on the cardiovascular system has been difficult to detect in prospective randomized trials. In addition, in some cases, hot flushes return despite the continuing use of long-term ERT. It is possible that estrogen treatment is physiologically appropriate, but the mode of estrogen administration might be problematic.
It is well known that progesterone or synthetic progestins downregulate progesterone receptors during continuous administration. Based on this observation, it was suggested that progesterone activity would be more efficient by “pulsed or intermittent administration” allowing both estrogen and progesterone receptors a chance for replenishment, as discussed in Casper, R. F. and Chapdelaine, A., Estrogen and interrupted progestin: a new concept for menopausal hormone replacement therapy, Am J Obstet Gynecol, 1993, April 168(4):1188-94; and in U.S. Pat. Nos. 5,108,995; 5,256,421; 5,276,022; 5,382,573; 5,422,119 and 5,585,370; and U.S. Application Ser. Nos. 60/369,629 and 60/369,707. All references are herein incorporated in their entirety.
In another approach discussed in Masamura et al., Estrogen deprivation causes estradiol hypersensitivity in human breast cancer cells, J Clin Endocrinol Metab 1995, October; 80(10):2918-25, it is postulated that enhanced sensitivity to estradiol (E2) may occur as a result of adaptation to low E2 levels after prolonged exposure to normal or supra-physiological levels of E2. Using a breast cancer cell line, they observed that breast cancer cells are able to adapt to low levels of estrogens by enhancing their sensitivity to E2.
In a study described in Wu et al., Regulation of the estrogen receptor and its messenger ribonucleic acid in the ovariectomized sheep myometrium and endometrium: the role of estradiol and progesterone, Biol Reprod 1996 October; 55(4):762-8, ovariectomized (OVX) non-pregnant sheep were used to analyze the role of estradiol and progesterone in the regulation of myometrial and endometrial estrogen receptor (ER) protein and ER mRNA in vivo. This group found that the effect of estradiol on ER expression is dose dependent. At supra-physiologic doses, estradiol inhibited ER expression, while physiologic concentrations of estradiol promoted ER expression.
In Clewell et al., Stimulus summation and tachyphylaxis in estrogen response in sheep, Am J Obstet Gynecol 1980 Nov. 1; 138 (5):485-93 (1980), it was shown that uterine blood flow is dependent on the initial estrogen concentration in the serum and the duration of the stimulus. It was concluded that prolonged, high-concentration exposure to estrogen results in tachyphylaxis.
In Medlock et al., Estradiol down-regulation of the rat uterine estrogen receptor, Proc Soc Exp Biol Med 1991 March; 196 (3):293-300, the effects of physiologic and pharmacologic doses of estradiol administered to adult ovariectomized rats via Silastic implants was examined. It was demonstrated that homologous down-regulation or loss of estrogen binding capacity was maximal at 24 hr and was completely reversible after implant removal. Of interest, the time required to recover from down-regulation was dose dependent. Medlock et al. concluded that estrogens can act as toxicants to the ER, especially when given chronically and in high doses. Subsequently, another study by Medlock et al. described in Medlock K L, et al., Short-term effects of physiological and pharmacological doses of estradiol on estrogen receptor and uterine growth, J Recept Res 1991; 11 (5):743-56, demonstrated that estradiol can down-regulate ER as early as 3 hours after exposure to pharmacologic doses and that the down-regulated state can be maintained by elevated E2 levels.
The present modes of delivering estrogen to postmenopausal women are oral, parenteral or transdermal. The oral administration exposes the body to a short daily peak of relatively high blood and hepatic estrogen levels, with rapid conversion to supra-physiological levels of less active estrone and inactive conjugated estrone sulphate. The parenteral and transdermal approaches deliver a steady level of estradiol with minimal hepatic metabolism. Epidemiological observations have to date not demonstrated major clinical differences between the various routes of estrogen administration. In current methods of administration, no time is given for ER replenishment by altering estrogen administration.
Prolonged administration of a constant dose of estradiol (either as continuous transdermal or daily oral bolus administration as given during HRT treatment) can decrease clinical response by down-regulation of estrogen receptors. This effect, as demonstrated in the present patent application, can be restored by intermittent administration of ultra-low doses of estrogen. It is reasonable to believe that by overcoming the possible estrogen receptor down-regulation effect observed with the conventional estrogen administration, the current proposed administration will result in better clinical response.
It is therefore desirable to provide an improved method to deliver estrogen to menopausal women and to overcome the limitations of the current methods.